CN116803376A - Compound guaiacol potassium sulfonate oral solution and preparation method thereof - Google Patents

Compound guaiacol potassium sulfonate oral solution and preparation method thereof Download PDF

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CN116803376A
CN116803376A CN202310975882.2A CN202310975882A CN116803376A CN 116803376 A CN116803376 A CN 116803376A CN 202310975882 A CN202310975882 A CN 202310975882A CN 116803376 A CN116803376 A CN 116803376A
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solution
oral solution
dissolving
methionine
promethazine hydrochloride
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CN116803376B (en
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余婷婷
孙维广
陈瑶
黄华晔
韦玉璐
潘静岚
胡玮婷
叶碧蕾
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Guangzhou Baiyunshan Xingqun Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

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Abstract

The invention relates to the technical field of oral liquid, in particular to a compound guaiacol potassium sulfonate oral solution and a preparation method thereof. The oral solution comprises the following components in percentage by weight and volume: 0.08-0.15% of promethazine hydrochloride, 2-3% of guaiacol potassium sulfonate, 0.5-1.5% of ammonium chloride, 0.93-1.55% of sodium citrate, 0.55-0.85% of citric acid, 0.15-0.45% of sodium benzoate and 0.05-0.45% of methionine.

Description

Compound guaiacol potassium sulfonate oral solution and preparation method thereof
Technical Field
The invention relates to the technical field of oral liquid, in particular to a compound guaiacol potassium sulfonate oral solution and a preparation method thereof.
Background
The compound guaiacol potassium sulfonate oral solution belongs to a compound preparation, is an antitussive and expectorant over-the-counter medicine, is used for treating cough and excessive phlegm caused by cold and allergic bronchitis, and consists of promethazine hydrochloride, guaiacol potassium sulfonate, ammonium chloride and other auxiliary materials.
Promethazine hydrochloride can competitively block a histamine Hl receptor to generate an antihistaminic effect, can resist telangiectasis caused by histamine, reduce permeability of the histamine, relieve wheezing caused by contraction of bronchial smooth muscle, and also has obvious central stabilization effect and a certain antitussive effect; the guaiacolsulfonate is a powerful expectorant, so that the secretion of the respiratory gland is increased, the sputum is diluted, and the expectoration is easy; ammonium chloride is a salt expectorant, and can reflectively increase secretion of respiratory tract mucous membrane glands, so that phlegm is easy to expectorate, and the removal of sticky phlegm is facilitated.
However, promethazine hydrochloride belongs to phenothiazine drugs, so that the characteristics are unstable, oxidative discoloration and degradation are easy, and the drugs are unstable. When the content of the main drugs of promethazine hydrochloride, guaiacolsulfonate and ammonium chloride is high, the compound guaiacolsulfonate oral solution has low stability, is easy to oxidize, is unfavorable for storage, is easy to precipitate after long-time placement, and has obviously deepened color after oxidation, and the use and safety of the medicine can be influenced by unstable medicine.
The Chinese patent application CN103142645A discloses a high-stability compound guaiacolsulfonic acid oral solution and a preparation method thereof, wherein the oral solution is prepared from promethazine hydrochloride, guaiacolsulfonic acid potassium, ammonium chloride, sodium citrate, citric acid, benzoic acid, ethylparaben, sucrose, caramel, litchi essence and banana essence serving as raw auxiliary materials, and an antioxidant, namely cysteine hydrochloride or vitamin C, and ethanol and water serving as solvents; the invention improves the defects of the traditional formula, and the antioxidant is added to effectively prevent the promethazine hydrochloride from being oxidized; however, the prescription of the oral solution is a low-concentration prescription, the stability of the high-concentration prescription needs to be further improved, and the prescription or the preparation process of the oral solution needs to be further optimized.
Chinese patent application CN106511373a discloses a compound guaiacolsulfonate oral solution and a preparation method thereof, wherein the compound guaiacolsulfonate oral solution comprises the following components: the composition comprises guaiacolsulfonate, promethazine hydrochloride, ammonium chloride, citric acid, sodium citrate, xylitol, benzoic acid, an antioxidant, a pH regulator, propylene glycol and purified water as solvents. The invention improves the stability of the oral solution by adjusting the proportion of propylene glycol and water, the pH value of the oral solution and adding the antioxidant and simultaneously by the specific adding sequence in the steps of the preparation method. However, the oral solution has the guaiacol content measured, and the stability of the product is still further improved.
The oxidation of the drug does not require the participation of other oxidants, and can cause an "autoxidation" only at room temperature. The antioxidant effect mainly affects each stage of the autoxidation process from different angles, and plays roles of a reducing agent, a retarder, a synergist and a chelating agent so as to provide electrons or effective hydrogen atoms for free radical acceptance, so that the chain reaction of autoxidation is mainly interrupted.
There are a number of water-soluble antioxidants in common use, including: sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, ascorbic acid, isoascorbic acid, thioglycerol, thiosorbic acid, thioglycolic acid, cysteine hydrochloride, alpha-thioglycerol, and the like. The antioxidant is used as a pharmaceutical adjuvant, and has general characteristics, and the product after oxidation and reduction is required to be harmless to human body, and has high antioxidation effect, and even at low concentration, the antioxidant has oxidation effect.
The compound guaiacol potassium sulfonate oral solution prepared and produced by the existing preparation method has higher impurity level, and the phenomena of unqualified solution color, reduced content, unqualified pH and the like easily occur during the stability period.
Therefore, it is necessary to develop a compound guaiacolsulfonate oral solution capable of solving the above technical problems and a preparation method thereof.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a compound potassium guaiacol sulfonate oral solution with stable active ingredient content, controlled related substances and lower content and a preparation method thereof.
The invention is realized by the following technical scheme:
the compound guaiacol potassium sulfonate oral solution comprises the following components in percentage by weight and volume: promethazine hydrochloride 0.08-0.15%, guaiacolsulfonate potassium 2-3%, ammonium chloride 0.5-1.5%, sodium citrate 0.93-1.55%, citric acid 0.55-0.85%, sodium benzoate 0.15-0.45% and methionine 0.05-0.45%.
The "weight and volume percent concentration" refers to the weight (in g) of the components contained in each 100mL of oral liquid. By taking promethazine hydrochloride 0.08-0.12% as an example, 0.08-0.12g promethazine hydrochloride is contained in every 100mL oral liquid.
Preferably, the oral solution comprises the following components in percentage by weight and volume: promethazine hydrochloride 0.1%, guaiacol sulfonic acid potassium 2.5%, ammonium chloride 1%, sodium citrate 1.3%, citric acid 0.6%, sodium benzoate 0.2% and methionine 0.2%.
Preferably, the oral solution further comprises at least one of ethanol, essence, pigment, and sweetener.
More preferably, the flavour comprises at least one of banana flavour and vanilla flavour.
More preferably, the pigment is caramel color.
More preferably, the sweetener is sucrose.
More preferably, the oral solution further comprises ethanol, flavors, colors, and sweeteners.
More preferably, the oral solution further comprises 0.2-0.4% banana essence, 0.3-0.5% vanilla essence and 0.005-0.015% caramel color; the oral solution also comprises 0.5-3% of ethanol and 49-53% of sucrose according to the weight and volume percentage concentration.
Preferably, the oral solution further comprises dithiothreitol 0.001-0.005% by weight volume percentage concentration.
Preferably, the oral solution comprises the following components: promethazine hydrochloride 0.08-0.15% (m/v), guaiacol potassium sulfonate 2-3% (m/v), ammonium chloride 0.5-1.5% (m/v), sodium citrate 0.93-1.55% (m/v), citric acid 0.55-0.85% (m/v), sodium benzoate 0.15-0.45% (m/v), methionine 0.05-0.45% (m/v), banana essence 0.2-0.4% (v/v), vanilla essence 0.3-0.5% (v/v), caramel color 0.005-0.015% (v/v), sucrose 49-53% (v/v), ethanol 0.5-3% (m/v). The balance being water.
"m/v" means the mass to volume ratio, mass in g and volume in mL.
The example of promethazine hydrochloride is 0.08-0.15% (m/v), which means that each 100mL of oral liquid contains 0.08-0.12g promethazine hydrochloride.
"v/v" means the volume ratio.
The invention also relates to a preparation method of the oral solution, which comprises the following steps:
(1) Dissolving sweetener in water, and filtering to obtain solution A;
(2) Dissolving ammonium chloride, citric acid and guaiacolsulfonate in water to obtain solution B;
(3) Adding the solution B into the solution A, and mixing to obtain a solution C;
(4) Dissolving sodium benzoate and sodium citrate in water, and mixing with the solution C to obtain solution D;
(5) Respectively dissolving methionine and promethazine hydrochloride with water, and adding into the solution D for mixing to obtain a solution E;
(6) Dissolving essence with ethanol, and mixing with solution E to obtain solution F;
(7) Adding pigment into solution F, and adding the rest water.
Preferably, in the step (1), the sweetener is taken, boiled and dissolved in water, and filtered while the sweetener is hot to obtain a solution A.
Preferably, the step (3) -step (6) mixing process employs stirring operation while adding.
Preferably, the mixing temperature is controlled from 30 to 60 ℃ in the steps (3) to (6).
Preferably, the pH of the liquid medicine is controlled to be 4.0-5.0 in the step (7).
Preferably, the preparation method further comprises the step (8) of filling the polyester bottle or the composite film material.
More preferably, nitrogen protection is performed during filling. The nitrogen is filled for protection, so that the risk of oxidation of the compound guaiacolsulfonate oral solution in shelf life is further reduced.
The beneficial effects of the invention are as follows:
according to the invention, through optimizing the formula composition and adding methionine, the oxidation of promethazine hydrochloride and guaiacolsulfonate can be effectively prevented, the stability of the compound guaiacolsulfonate oral solution in the placing process is improved, and meanwhile, the content of related substances is also obviously reduced.
According to the invention, in the preparation process, the raw material adding sequence of the compound potassium guaiacol sulfonate oral solution is optimized, the mixing temperature of the liquid medicine is controlled to be between 30 and 60 ℃, the final pH control (pH is 4.0 to 5.0) of the liquid medicine is regulated, and the nitrogen is filled for protection and filling, so that the risk of oxidation of the liquid medicine in the storage process of the compound potassium guaiacol sulfonate oral solution is reduced. After the prescription composition and the preparation process are improved, the product quality of the compound guaiacolsulfonate oral solution can be improved, the content of related substances of the product is lower on the basis of the prior art, the property is stable, and the product quality stability in the effective period is further improved.
In addition, the inventor unexpectedly found that the synergistic effect of methionine and dithiothreitol in improving the stability of the compound guaiacolsulfonate oral solution is remarkable, and the stability of the content of the active ingredients can be further improved, and the content of related substances can be reduced.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Example 1
A preparation method of a compound guaiacol potassium sulfonate oral solution comprises the following steps:
(1) Accurately weighing the following components: promethazine hydrochloride 0.1% (m/v), potassium guaiacolsulfonate 2.5% (m/v), ammonium chloride 1% (m/v), sodium citrate 1.3% (m/v), citric acid 0.6% (m/v), sodium benzoate 0.2% (m/v), banana essence 0.3% (v/v), vanilla essence 0.4% (v/v), caramel color 0.01% (v/v), sucrose 51% (m/v), methionine 0.2% (m/v), ethanol 2% (m/v).
(2) Adding purified water into sucrose with prescription amount, boiling, dissolving, filtering with bag filter, and adding into blending tank.
(3) Mixing and dissolving ammonium chloride, citric acid and guaiacol potassium sulfonate with purified water, adding into a blending tank, stirring while controlling the temperature of the liquid medicine to 45deg.C. Wherein the ammonium chloride is dried and the feeding amount is calculated.
(4) Dissolving sodium benzoate and sodium citrate in purified water, adding into a blending tank, stirring, and controlling the temperature of the liquid medicine to 45 ℃.
(5) Taking the prescription amount of methionine and promethazine hydrochloride, respectively stirring and dissolving the methionine and promethazine hydrochloride by purified water, then putting the methionine and promethazine hydrochloride into a blending tank, stirring the methionine and promethazine hydrochloride while adding the purified water, and controlling the temperature of the liquid medicine to be 45 ℃.
(6) And (3) taking the prescription amount of vanilla essence and banana essence, dissolving the vanilla essence and banana essence in ethanol, adding the dissolved banana essence into a blending tank, stirring the materials, and controlling the temperature of the liquid medicine to be 45 ℃.
(7) Adding caramel color, adjusting color to light brown, adding purified water to volume, stirring, and controlling pH to 4.5.
(8) Filling with a polyester/aluminum/polyester/polyethylene oral liquid medicinal composite film, and filling nitrogen for protection in the filling process.
Example 2
A preparation method of a compound guaiacol potassium sulfonate oral solution comprises the following steps:
(1) Accurately weighing the following components: promethazine hydrochloride 0.08% (m/v), potassium guaiacolsulfonate 2% (m/v), ammonium chloride 0.5% (m/v), sodium citrate 0.93% (m/v), citric acid 0.55% (m/v), sodium benzoate 0.15% (m/v), banana essence 0.2% (v/v), vanilla essence 0.3% (v/v), caramel color 0.005% (v/v), sucrose 49% (m/v), methionine 0.05% (m/v), ethanol 0.5% (m/v), and the balance of purified water.
(2) Adding purified water into sucrose with prescription amount, boiling, dissolving, filtering with bag filter, and adding into blending tank.
(3) Mixing and dissolving ammonium chloride, citric acid and guaiacol potassium sulfonate with purified water, adding into a blending tank, stirring while controlling the temperature of the liquid medicine to 30deg.C. Wherein the ammonium chloride is dried and the feeding amount is calculated.
(4) Dissolving sodium benzoate and sodium citrate in purified water, adding into a blending tank, stirring, and controlling the temperature of the liquid medicine to 30deg.C.
(5) Taking the prescription amount of methionine and promethazine hydrochloride, respectively stirring and dissolving the methionine and promethazine hydrochloride by purified water, then putting the methionine and promethazine hydrochloride into a blending tank, stirring the methionine and promethazine hydrochloride while adding the purified water, and controlling the temperature of the liquid medicine to be 30 ℃.
(6) And (3) taking the prescription amount of vanilla essence and banana essence, dissolving the vanilla essence and banana essence in ethanol, adding the dissolved banana essence into a blending tank, stirring the materials, and controlling the temperature of the liquid medicine to be 30 ℃.
(7) Adding caramel color, mixing to light brown, adding purified water to batch, stirring, and controlling pH to 4.0.
(8) Filling with a polyester/aluminum/polyester/polyethylene oral liquid medicinal composite film, and filling nitrogen for protection in the filling process.
Example 3
A preparation method of a compound guaiacol potassium sulfonate oral solution comprises the following steps:
(1) Accurately weighing the following components: promethazine hydrochloride 0.15% (m/v), guaiacol sulfonic acid potassium 3% (m/v), ammonium chloride 1.5% (m/v), sodium citrate 1.55% (m/v), citric acid 0.85% (m/v), sodium benzoate 0.45% (m/v), banana essence 0.4% (v/v), vanilla essence 0.5% (v/v), caramel color 0.015% (v/v), sucrose 53% (m/v), methionine 0.45% (m/v), ethanol 3% (m/v), and the balance of purified water.
(2) Adding purified water into sucrose with prescription amount, boiling, dissolving, filtering with bag filter, and adding into blending tank.
(3) Mixing and dissolving ammonium chloride, citric acid and guaiacol potassium sulfonate with purified water, adding into a blending tank, stirring while controlling the temperature of the liquid medicine to 60 ℃. Wherein the ammonium chloride is dried and the feeding amount is calculated.
(4) Dissolving sodium benzoate and sodium citrate in purified water, adding into a blending tank, stirring, and controlling the temperature of the liquid medicine to 60 ℃.
(5) Taking the prescription amount of methionine and promethazine hydrochloride, respectively stirring and dissolving the methionine and promethazine hydrochloride by purified water, then putting the methionine and promethazine hydrochloride into a blending tank, stirring the methionine and promethazine hydrochloride while adding the purified water, and controlling the temperature of the liquid medicine to be 60 ℃.
(6) And (3) taking the prescription amount of vanilla essence and banana essence, dissolving the vanilla essence and banana essence in ethanol, adding the dissolved banana essence into a blending tank, stirring the materials, and controlling the temperature of the liquid medicine to be 60 ℃.
(7) Adding caramel color, mixing to light brown, adding purified water to batch, stirring, and controlling pH to 5.0.
(8) Filling with a polyester/aluminum/polyester/polyethylene oral liquid medicinal composite film, and filling nitrogen for protection in the filling process.
Example 4
The only difference from example 1 is that methionine 0.2% (m/v) was replaced by methionine 0.195% (m/v), dithiothreitol 0.005% (m/v), and the specific formulation was as follows:
promethazine hydrochloride 0.1% (m/v), guaiacol sulfonic acid potassium 2.5% (m/v), ammonium chloride 1% (m/v), sodium citrate 1.3% (m/v), citric acid 0.6% (m/v), sodium benzoate 0.2% (m/v), banana essence 0.3% (v/v), vanilla essence 0.4% (v/v), caramel color 0.01% (v/v), sucrose 51% (m/v), methionine 0.195% (m/v), dithiothreitol 0.005% (m/v), ethanol 2% (m/v), and the balance purified water.
The other conditions were the same as in example 1.
Comparative example 1
The difference from example 1 is only that methionine is replaced by 0.2% (m/v) to cysteine hydrochloride 0.2% (m/v), the remaining conditions being identical.
Comparative example 2
The difference from example 4 is only that methionine is absent, only 0.2% (m/v) dithiothreitol is present, the remaining conditions being the same.
Comparative example 3
The difference from example 1 is only that 0.2% (m/v) of methionine is not added, the remaining conditions are the same.
Comparative example 4
The difference from example 1 is only that the mixing temperatures in step (3) to step (6) (70 ℃ C.) and the pH in step (7) are different (the pH is 5.5 by adjusting the raw material amounts: 0.06% (m/v) of citric acid, 0.4% (m/v) of sodium citrate, 0.04% (m/v) of sodium hydroxide), and the other conditions are the same.
Test example 1 accelerated stability test
(1) The method comprises the following steps: according to the stability guidance test principle of the quality standard WS-10001- (HD-1100) -2002-2022 and the edition 2020 of Chinese pharmacopoeia, under the condition of the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5 percent, according to the key investigation items of the stability of the oral solution, the items of the properties, the pH value, the relative density, the active ingredient content, the microorganism limit and the like of the oral solution are respectively inspected by sampling and inspection at the end of 1 month, 2 months, 3 months and 6 months. The results are shown in Table 1.
TABLE 1 stability examination results (temperature 40.+ -. 2 ℃ C., relative humidity 75%.+ -. 5%)
(2) Results: from the experimental data in Table 1, it can be seen that the product produced by the process of the present invention can maintain the stability of promethazine hydrochloride under severe conditions.
Test example 2 long term stability test
(1) The method comprises the following steps: according to the stability guidance test principle of the quality standard WS-10001- (HD-1100) -2002-2022 and the edition 2020 of Chinese pharmacopoeia, under the conditions of 25 ℃ plus or minus 5 ℃ and 60% plus or minus 5% relative humidity, according to the stability key investigation project of oral solution, the projects of the characteristics, the relative density, the content of related substances, the microbial limit and the like are investigated by sampling and testing at the end of the 0 th month, the 3 rd month, the 6 th month, the 9 th month, the 12 th month and the 18 th month respectively. The results are shown in Table 2.
(2) Results: experimental data shows that the product produced by the process can still maintain the stability of promethazine hydrochloride under the storage condition.
TABLE 2 stability examination results (temperature 25 ℃ C.+ -. 2 ℃ C., relative humidity 60%.+ -. 5%)
Test example 3
And detecting the promethazine hydrochloride related substances at 40+/-2 ℃ and 75+/-5% relative humidity for 3 months and 6 months.
The method for detecting the promethazine hydrochloride related substances comprises the following steps: high performance liquid chromatography, octadecylsilane chemically bonded silica column (4.6mm×150mm), 0.01mol/L diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B. Gradient elution was carried out at a flow rate of 1.0mL min -1 The method comprises the steps of carrying out a first treatment on the surface of the The detection wavelength is 249nm, the column temperature is 30 ℃, the sample solution and the reference substance solution (the promethazine hydrochloride reference substance, the promethazine hydrochloride impurity A reference substance, the promethazine hydrochloride impurity B reference substance, the promethazine hydrochloride impurity C reference substance and the promethazine hydrochloride impurity D reference substance) are precisely measured and prepared, 20 mu L of each solution is injected into a liquid chromatograph. The test results are shown in Table 3.
HPLC gradient elution procedure:
TABLE 3 detection results of promethazine hydrochloride related substances (temperature 40 ℃ C.+ -2 ℃ C., relative humidity 75% + -5%)
Description of impurities:
impurity a-promethazine EP impurity a;
impurity B-promethazine EP impurity B;
impurity C-promethazine EP impurity C;
impurity D-promethazine EP impurity D.
As can be seen from Table 3, the control of each impurity and the total impurities in example 1 is obviously better than that in comparative examples 1 and 3, and the total impurities can be controlled to be less than 2.50% under the acceleration condition that the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5%.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.

Claims (10)

1. The compound guaiacol potassium sulfonate oral solution is characterized by comprising the following components in percentage by weight and volume: promethazine hydrochloride 0.08-0.15%, guaiacolsulfonate potassium 2-3%, ammonium chloride 0.5-1.5%, sodium citrate 0.93-1.55%, citric acid 0.55-0.85%, sodium benzoate 0.15-0.45% and methionine 0.05-0.45%.
2. The oral solution of claim 1, comprising the following components in weight percent concentration: promethazine hydrochloride 0.1%, guaiacol sulfonic acid potassium 2.5%, ammonium chloride 1%, sodium citrate 1.3%, citric acid 0.6%, sodium benzoate 0.2% and methionine 0.2%.
3. The oral solution of claim 1, further comprising at least one of ethanol, flavor, color, and sweetener.
4. The oral solution of claim 3, wherein the flavor comprises at least one of banana flavor and vanilla flavor; the pigment is caramel color; the sweetener is sucrose.
5. The oral solution of claim 4, further comprising, by volume percent, banana essence 0.2-0.4%, vanilla essence 0.3-0.5%, caramel color 0.005-0.015%; the beverage also comprises 0.5-3% of ethanol and 49-53% of sucrose according to the weight volume percentage concentration.
6. The oral solution of any one of claims 1-5, further comprising dithiothreitol at a concentration of 0.001-0.005% by weight volume.
7. The method for preparing an oral solution according to any one of claims 3 to 5, comprising the steps of:
(1) Dissolving sweetener in water, and filtering to obtain solution A;
(2) Dissolving ammonium chloride, citric acid and guaiacolsulfonate in water to obtain solution B;
(3) Adding the solution B into the solution A, and mixing to obtain a solution C;
(4) Dissolving sodium benzoate and sodium citrate in water, and mixing with the solution C to obtain solution D;
(5) Respectively dissolving methionine and promethazine hydrochloride with water, and adding into the solution D for mixing to obtain a solution E;
(6) Dissolving essence with ethanol, and mixing with solution E to obtain solution F;
(7) Adding pigment into solution F, and adding the rest water.
8. The preparation method according to claim 7, wherein in the step (1), the sweetener is taken, boiled and dissolved in water, and filtered while hot to obtain a solution A; step (3) -step (6) controlling the mixing temperature to be 30-60 ℃; and (7) controlling the pH value to be 4.0-5.0.
9. The method of manufacturing according to claim 7, further comprising step (8): and (5) filling the polyester bottle or the composite film material.
10. The method of claim 9, wherein the nitrogen is filled during the filling process.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054012A1 (en) * 2000-06-06 2004-03-18 Francois Dietlin Method for obtaining aqueous formulations of oxidation-sensitive active principles
CN103142645A (en) * 2013-03-26 2013-06-12 广东南国药业有限公司 High stability composite guaiacol phenolsulfonic acid oral liquid and preparation method thereof
CN103637980A (en) * 2013-11-26 2014-03-19 天津药业集团新郑股份有限公司 Preparation method for promethazine hydrochloride injection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054012A1 (en) * 2000-06-06 2004-03-18 Francois Dietlin Method for obtaining aqueous formulations of oxidation-sensitive active principles
CN103142645A (en) * 2013-03-26 2013-06-12 广东南国药业有限公司 High stability composite guaiacol phenolsulfonic acid oral liquid and preparation method thereof
CN103637980A (en) * 2013-11-26 2014-03-19 天津药业集团新郑股份有限公司 Preparation method for promethazine hydrochloride injection

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